Effect of serotonin4 (5-HT4) receptor agonists on aldosterone secretion in idiopathic hyperaldosteronism.
Serotonin (5-HT) stimulates aldosterone secretion in man through 5-HT4 receptors positively coupled to adenylyl cyclase. In particular, it has been shown that oral administration of a single dose of the 5-HT4 receptor agonist cisapride induces a significant increase in plasma aldosterone levels (PAL) in healthy volunteers. Idiopathic hyperaldosteronism (IH) is a rare disorder characterized by hypertension, hypokalemia and bilateral adrenal hypersecretion of aldosterone. In patients with IH, administration of the 5-HT precursor 5-hydroxytryptophan (5-HTP) is followed by a significant increase in PAL. 5-HTP-induced aldosterone secretion has been attributed to the activation of central serotonergic pathways. The aim of the present study was to evaluate the effect of the oral administration of a single dose of cisapride (10 mg) on aldosterone secretion in 15 patients with IH, in a simple blind fashion versus placebo. Cisapride induced a significant increase in PAL but did not affect renin, cortisol and potassium levels. The present study demonstrates that 5-HT4 receptor agonists are able to stimulate aldosterone secretion in patients with IH. These data also indicate that hyperplastic glomerulosa tissue, like normal glomerulosa cells, expresses a functional 5-HT4 receptor. Therefore, 5-HT4 receptor antagonists may represent a new approach in the treatment of primary hyperaldosteronism.


An integrated approach (CLuster Analysis Integration Method) to combine expression data and protein-protein interaction networks in agrigenomics: application on Arabidopsis thaliana.
Experimental co-expression data and protein-protein interaction networks are frequently used to analyze the interactions among genes or proteins. Recent studies have investigated methods to integrate these two sources of information. We propose a new method to integrate co-expression data obtained through DNA microarray analysis (MA) and protein-protein interaction (PPI) network data, and apply it to Arabidopsis thaliana. The proposed method identifies small subsets of highly interacting proteins. Based on the analysis of the basis of co-localization and mRNA developmental expression, we show that these groups provide important biological insights; additionally, these subsets are significantly enriched with respect to KEGG Pathways and can be used to predict successfully whether proteins belong to known pathways. Thus, the method is able to provide relevant biological information and support the functional identification of complex genetic traits of economic value in plant agrigenomics research. The method has been implemented in a prototype software tool named CLAIM (CLuster Analysis Integration Method) and can be downloaded from http://bio.cs.put.poznan.pl/research_fields . CLAIM is based on the separate clustering of MA and PPI data; the clusters are merged in a special graph; cliques of this graph are subsets of strongly connected proteins. The proposed method was successfully compared with existing methods. CLAIM appears to be a useful semi-automated tool for protein functional analysis and warrants further evaluation in agrigenomics research.


Draft Genome Sequence of Natronolimnobius baerhuensis CGMCC 1.3597T, an Aerobic Haloalkaliphilic Archaeon Isolated from a Soda Lake.
The haloalkaliphilic archaeon Natronolimnobius baerhuensis was isolated from a soda lake in Inner Mongolia (China), growing optimally at about 20% NaCl and pH 9.0. The draft genome consists of approximately 3.91 Mb and contains 3,810 predicted genes. Some genes that regulate intracellular osmotic stress and pH homeostasis were identified, providing insight into specific adaptations to this double-extreme environment.


Role of calcium antagonists in the treatment of essential hypertension.
The calcium antagonists, diltiazem and nifedipine, are effective in mild-to-moderate chronic essential hypertension. The overall responder rate is 80%. Diastolic blood pressure is lowered by 10-15% at rest and during exercise. Systolic blood pressure is reduced only at rest. Heart rate may be unchanged by nifedipine and lowered by diltiazem. Both drugs lead to a decrease of peripheral resistance by 15-20% at rest and 30% during work. As a consequence of afterload reduction, cardiac output, stroke index, and stroke work index increased by 17, 21, and 7% with nifedipine and 34, 26, and 20% with diltiazem. During exercise, these changes are even more pronounced. However, pulmonary artery pressure and pulmonary vascular resistance are reduced only by nifedipine, not by diltiazem. Presumably due to this combined preload and afterload reduction, nifedipine therapy is associated with a reflex activation of the sympathetic nervous system in all cases, with an increase in norepinephrine plasma concentration and, sometimes, tachycardia. Diltiazem, however, has the advantage of being a potent blood pressure-lowering agent, with afterload reduction and increased stroke index, with less pronounced catecholamine increase, and without tachycardia. Side effects with this drug are rare, and long-term therapy is well tolerated.


Potent activity of 5-fluoro-2'-deoxyuridine and related compounds against thymidine kinase-deficient (TK-) herpes simplex virus: targeted at thymidylate synthase.
5-Fluorouracil, 5-fluorouridine (FUrd), 5-fluoro-2'-deoxyuridine (FdUrd), 5-fluorocytidine (FCyd), 5-fluoro-2'-deoxycytidine (FdCyd), 5-trifluoro-2'-deoxythymidine (F3dThd), and the 5'-monophosphates and 3',5'-cyclic monophosphates thereof were found to inhibit thymidine kinase-deficient (TK-) mutant strains of herpes simplex virus (HSV) at a much lower concentration than the wild-type (TK+) HSV strains. Other 5-substituted 2'-deoxyuridines that have previously been recognized as potent thymidylate synthase inhibitors behaved in a similar fashion. The activity of FdUrd, FdCyd, F3dThd, and their 3',5'-cyclic monophosphates against TK-HSV was readily reversed by 2'-deoxythymidine (dThd) but not by 2'-deoxyuridine (dUrd). These compounds also inhibited the incorporation of [6-3H]dUrd into DNA at a concentration which was up to 5 orders of magnitude lower than the concentration at which the incorporation of [methyl-3H] dThd was inhibited. Thus, while not being a target for the well established anti-HSV compounds in TK+HSV-infected cells, thymidylate synthase appears to be an important target in TK-HSV-infected cells. In addition to dTMP synthase, TK-HSV-infected cells appear to reveal other therapeutically exploitable targets such as OMP decarboxylase (towards pyrazofurin), CTP synthase (towards carbodine and its cyclopentenyl analogue), dihydrofolate reductase (towards methotrexate), and S-adenosylhomocysteine hydrolase (towards neplanocins).


Structurally interdependent and independent regions of allelic polymorphism in class II MHC molecules. Implications for Ia function and evolution.
Possible interactions between regions of allelic polymorphism in the alpha- and beta-chains of class II MHC molecules were examined by measuring the efficiency of surface expression and the reactivity with mAb of wild-type and recombinant A alpha A beta-chain pairs from the b, d, and k haplotypes. These studies revealed regions of polymorphism within the alpha- and beta-chains that interact with complementary regions in the other chain. Unexpectedly, almost all the variable segments of both the class II MHC alpha- and beta-chains either directly contributed to or were near sites of interchain interactions. The exception was the beta HV3 (hypervariable (HV] segment (residues 61-71), which appeared to neither participate in nor be affected by interchain interactions. This division of the MHC molecule into interacting vs independent regions of allelic structural variation suggests that mutagenesis experiments involving the beta HV3 segment can be analyzed in a straightforward manner, as such mutations appear unlikely to alter the conformation of other molecular segments. Furthermore, functions attributed to the beta HV3 segment either experimentally or by population analysis should have a high probability of transfer by beta HV3 exchange (either experimentally or evolutionarily), because epitopes assigned to this region of the molecule are not affected by sequences outside this segment. This is of special importance because of the apparent involvement of this region in defining a potential site of interaction with antigenic peptides and TCR. In contrast, almost all other variable segments of the MHC molecule appear to have the capacity to contribute to interactions involving at least one other variable segment. This suggests not only that the experimental analysis of the contributions of these regions to various functions requires a consideration of inter- and intrachain interaction, but also that the transfer of function by genetic exchange of these structurally dependent regions is unpredictable. Selection must therefore operate on these interacting HV segments in the context of the complete alpha beta heterodimer. These results support our earlier arguments for cis-co-evolution of alpha- and beta-chain polymorphism and the absence of selection for F1 (hybrid) class II molecules. Finally, asymmetries observed in the contributions of particular pairs of HV segments to the efficient expression of Ia alpha beta heterodimers provide a basis for understanding mechanistically how cis-co-evolution may have occurred.


Restriction enzyme analysis of mitochondrial DNAs of petite mutants of yeast: classification of petites, and deletion mapping of mitochondrial genes.
We have analyzed the restriction digest patterns of the mitochondrial DNA from 41 cytoplasmic petite strains of Saccharomyces cerevisiae, that have been extensively characterized with respect to genetic markers. Each mitochondrial DNA was digested with seven restriction endonucleases (EcoRI, HPaI, HindIII, BamHI, HhaI, SalI, and PstI) which together make 41 cuts in grande mitochondrial DNA and for which we have derived fragment maps. The petite mitochondrial DNAs were also analyzed with HpaII, HaeIII, and AluI, each of which makes more than 80 cleavages in grande mitochondrial DNA. On the basis of the restriction patterns observed (i.e., only one fragment migrating differently from grande for a single deletion, and more than one for multiple deletions) and by comparing petite and grande mitochondrial DNA restriction maps, the petite clones could be classified into two main groups: (1) petites representing a single deletion of grande mitochondrial DNA and (2) petites containing multiple deletions of the grande mitochondrial DNA resulting in rearranged sequences. Single deletion petites may retain a large portion of the grande mitochondrial genome or may be of low kinetic cimplexity. Many petites which are scored as single continuous deletions by genetic criteria were later demonstrated to be internally deleted by restriction endonuclease analysis. Heterogeneous sequences, manifested by the presence of sub-stoichiometric amounts of some restriction fragments, may accompany the single or multiple deletions. Single deletions with heterogeneous sequences remain useful for mapping if the low concentration sequences represent a subset of the stoichiometric bands. Using a group of petites which retain single continuous regions of the grande mitochondrial DNA, we have physically mapped antibiotic resistance and mit- markers to regions of the grande restriction map as follows: C (99.3--1.4 map units)--OXI-1 (2.5--15.7)--OXI-2 (18.5--25)--P (28.1--34.2)--OXI-3 (32.2--61.2--OII (60--62)--COB (64.6--80.8--0I (80.4--85.7)--E (95--98.9).


The genetic basis of cognition.
The molecular characterization of single-gene disorders or chromosomal abnormalities that result in a cognitive abnormality (predominantly mental retardation) and of the genetic variants responsible for variation in intellectual abilities (such as IQ, language impairment and dyslexia) is expected to provide new insights into the biology of human cognitive processes. To date this hope has not been realized. Success in finding mutations that give rise to mental retardation has not been matched by advances in our understanding of how genes influence cognition. In contrast, the use of engineered mutations in mice to study models of learning and memory has cast new light on the molecular basis of memory. A comparison of studies of human and mouse mutations indicates the limitations of current genetic approaches to the understanding of human cognition. It is essential to interpret a mutation's effect within a well-characterized neural system; mutations can be used to define gene function only when the mutation has an effect on a system whose constituents form a serial causal chain, such as the molecular components of a signal transduction pathway. Typically, however, genetic mutations with a cognitive and behavioural phenotype are characterized by specific effects on different systems whose inter-relationships are unknown. Genetic approaches are currently limited to exploring neuronal function; it is not yet clear whether they will throw light on how neuronal connections give rise to cognitive processes. We need a much greater integration of different levels of understanding of cognition in order to exploit the genetic discoveries. In short, a rapprochement between molecular and systems neuroscience is required.


Transcription factor E2F and cyclin E-Cdk2 complex cooperate to induce chromosomal DNA replication in Xenopus oocytes.
Although no chromosomal DNA replication actually occurs during Xenopus oocyte maturation, the capability develops during the late meiosis I (MI) phase in response to progesterone. This ability, however, is suppressed by Mos proteins and maturation/mitosis promoting factor during the second meiosis phase (meiosis II; MII) until fertilization. Inhibition of RNA synthesis by actinomycin D during early MI prevented induction of the replication ability, but did not interfere with initiation of the meiotic cell cycle progression characterized by oscillation of the maturation/mitosis promoting factor activity and germinal vesicle breakdown. Microinjection of recombinant proteins such as dominant-negative E2F or universal Cdk inhibitors, p21 and p27, but not wild type human E2F-1 or Cdk4-specific inhibitor, p19, into maturing oocytes during MI abolished induction of the DNA replication ability. Co-injection of human E2F-1 and cyclin E proteins into immature oocytes allowed them to initiate DNA replication even in the absence of progesterone treatment. Injection of cyclin E alone, which was sufficient to activate endogenous Cdk2 kinase, failed to induce DNA replication. Moreover, the activation of Cdk2 was not affected under the conditions where DNA replication was blocked by actinomycin D. Thus, like somatic cells, both activities of E2F and cyclin E-Cdk2 complex are required for induction of the DNA replication ability in maturing Xenopus oocytes, and enhancement of both activities enables oocytes to override DNA-replication inhibitory mechanisms that specifically lie in maturing oocytes.


A new perspective on Bruch's membrane and the retinal pigment epithelium.
Trypsin digestion of retinal pigment epithelium is a technique that bares Bruch's membrane, to allow topographical examination by scanning electron microscopy. Twenty-five human eyes were examined. The zonula occludens of the pigment epithelium was clearly seen as a surface feature, but attachment plaques at the sides and base were not visible. The adhesion between the pigment epithelium and the basal lamina was stronger than between the basal lamina and the rest of Bruch's membrane. Surface features of the basal lamina, inner collagenous zone, elastic layer, and outer collagenous zone were seen in a way that previously required an artist's representation constructed from microscopic sections.


[Cardiac comorbidity in patients with chronic obstructive pulmonary disease: diagnosis and economics].
To provide a clinical and economic rationale for the comprehensive examination of patients with chronic obstructive pulmonary disease (COPD), by using functional and ultrasound methods for the early detection of cardiac comorbidity. Three hundred and sixteen patients (33 with COPD, 44 with COPD + hypertension, 73 with COPD + coronary heart disease (CHD), 36 with hypertension, 50 with CHD, 19 with asthma, and 28 with asthma + hypertension) and 33 apparently healthy individuals were examined using 611 indicators obtained directly or by calculation during echocardiography, carotid artery duplex scanning, and 24-hour electrocardiographic (ECG) and blood pressure (BP) monitoring. Cardiovascular diseases develop in patients with COPD in its early stages. In cardiac comorbidity, the length of hospital stay increases by 1-1.5 days in patients with COPD; the number of people admitted to hospital more than once every 3 years rises from 14 to 28%; the cost of a pharmacotherapy cycle is 1.35- and 2.95-fold higher when COPD is concurrent with hypertension and CHD, respectively. In addition to ECG and spirometry, the management standard for patients with COPD should include echocardiography, 24-hour ECG and BP monitoring, and, according to their results, carotid artery duplex scanning.


ELISA D-dimer measurement for the clinical suspicion of pulmonary embolism in the emergency department: one-year observational study of the safety profile and physician's prescription.
To validate the safety profile of a rapid ELISA D-dimer as the first diagnostic step in the clinical suspicion of pulmonary embolism (PE) in outpatients admitted to an emergency department (ED), and to retrospectively evaluate the appropriateness of the physician's prescription. An observational study of all patients admitted to the ED of an urban university teaching hospital with signs and symptoms justifying the prescription of a rapid ELISA D-dimer measurement (Vidas; Biomerieux; France) as the first line diagnostic test for PE. Acute PE was established or excluded according to an appropriate combination of the D-dimer concentration, the lung scintigraphy, the spiral computerized tomography (spiral CT), the venous ultrasonography, and the arteriography in case of uncertain results. All patients with D-dimer values under the cut-off point of 500 ng/ml were followed up after 6 months. 395 patients were studied. A normal D-dimer concentration < 500 ng/ml was found in 179 patients (45% of the cohort). The retrospective analysis showed that none of these patients were found to have a high pre-test clinical probability. None of these 179 patients received anticoagulation nor displayed a PE event during a 6-month period (negative predictive value 100%; 95% CI, 98.0 to 100%; sensitivity 100%; 95% CI, 90.3 to 100%). Among the 216 patients (55%) with D-dimer values above 500 ng/ml, PE was confirmed in 32 cases, for a prevalence of the disease of 8.1%. Eighty-six patients (22%) had no additional testing in spite of positive D dimer values > 500 ng/ml, pointing out a 22% rate of inappropriate use of the D-dimer measurement. This observational study confirms that a normal rapid ELISA D-dimer value (< 500 ng/ml) used as a first diagnostic step in ruling out the diagnosis of PE is a safe clinical practice when the pre-test clinical probability is low or intermediate. Nevertheless, the low prevalence rate of the disease (8.1%) suggests a potential overused and inappropriate prescription.


Harmonization of CSF and imaging biomarkers in Alzheimer's disease: Need and practical applications for genetics studies and preclinical classification.
In Alzheimer's disease (AD) research, cerebrospinal fluid (CSF) Amyloid beta (Aβ), Tau and pTau are the most accepted and well validated biomarkers. Several methods and platforms exist to measure those biomarkers, leading to challenges in combining data across studies. Thus, there is a need to identify methods that harmonize and standardize these values. We used a Z-score based approach to harmonize CSF and amyloid imaging data from multiple cohorts and compared GWAS results using this approach with currently accepted methods. We also used a generalized mixture model to calculate the threshold for biomarker-positivity. Based on our findings, our normalization approach performed as well as meta-analysis and did not lead to any spurious results. In terms of dichotomization, cutoffs calculated with this approach were very similar to those reported previously. These findings show that the Z-score based harmonization approach can be applied to heterogeneous platforms and provides biomarker cut-offs consistent with the classical approaches without requiring any additional data.


Characterization of C1-metabolizing prokaryotic communities in methane seep habitats at the Kuroshima Knoll, southern Ryukyu Arc, by analyzing pmoA, mmoX, mxaF, mcrA, and 16S rRNA genes.
Samples from three submerged sites (MC, a core obtained in the methane seep area; MR, a reference core obtained at a distance from the methane seep; and HC, a gas-bubbling carbonate sample) at the Kuroshima Knoll in the southern Ryuku arc were analyzed to gain insight into the organisms present and the processes involved in this oxic-anoxic methane seep environment. 16S rRNA gene analyses by quantitative real-time PCR and clone library sequencing revealed that the MC core sediments contained abundant archaea (approximately 34% of the total prokaryotes), including both mesophilic methanogens related to the genus Methanolobus and ANME-2 members of the Methanosarcinales, as well as members of the delta-Proteobacteria, suggesting that both anaerobic methane oxidation and methanogenesis occurred at this site. In addition, several functional genes connected with methane metabolism were analyzed by quantitative competitive-PCR, including the genes encoding particulate methane monooxygenase (pmoA), soluble methane monooxygenase (mmoX), methanol dehydrogenese (mxaF), and methyl coenzyme M reductase (mcrA). In the MC core sediments, the most abundant gene was mcrA (2.5 x 10(6) copies/g [wet weight]), while the pmoA gene of the type I methanotrophs (5.9 x 10(6) copies/g [wet weight]) was most abundant at the surface of the MC core. These results indicate that there is a very complex environment in which methane production, anaerobic methane oxidation, and aerobic methane oxidation all occur in close proximity. The HC carbonate site was rich in gamma-Proteobacteria and had a high copy number of mxaF (7.1 x 10(6) copies/g [wet weight]) and a much lower copy number of the pmoA gene (3.2 x 10(2) copies/g [wet weight]). The mmoX gene was never detected. In contrast, the reference core contained familiar sequences of marine sedimentary archaeal and bacterial groups but not groups specific to C1 metabolism. Geochemical characterization of the amounts and isotopic composition of pore water methane and sulfate strongly supported the notion that in this zone both aerobic methane oxidation and anaerobic methane oxidation, as well as methanogenesis, occur.


Trade-offs in thermal adaptation: the need for a molecular to ecological integration.
Through functional analyses, integrative physiology is able to link molecular biology with ecology as well as evolutionary biology and is thereby expected to provide access to the evolution of molecular, cellular, and organismic functions; the genetic basis of adaptability; and the shaping of ecological patterns. This paper compiles several exemplary studies of thermal physiology and ecology, carried out at various levels of biological organization from single genes (proteins) to ecosystems. In each of those examples, trade-offs and constraints in thermal adaptation are addressed; these trade-offs and constraints may limit species' distribution and define their level of fitness. For a more comprehensive understanding, the paper sets out to elaborate the functional and conceptual connections among these independent studies and the various organizational levels addressed. This effort illustrates the need for an overarching concept of thermal adaptation that encompasses molecular, organellar, cellular, and whole-organism information as well as the mechanistic links between fitness, ecological success, and organismal physiology. For this data, the hypothesis of oxygen- and capacity-limited thermal tolerance in animals provides such a conceptual framework and allows interpreting the mechanisms of thermal limitation of animals as relevant at the ecological level. While, ideally, evolutionary studies over multiple generations, illustrated by an example study in bacteria, are necessary to test the validity of such complex concepts and underlying hypotheses, animal physiology frequently is constrained to functional studies within one generation. Comparisons of populations in a latitudinal cline, closely related species from different climates, and ontogenetic stages from riverine clines illustrate how evolutionary information can still be gained. An understanding of temperature-dependent shifts in energy turnover, associated with adjustments in aerobic scope and performance, will result. This understanding builds on a mechanistic analysis of the width and location of thermal windows on the temperature scale and also on study of the functional properties of relevant proteins and associated gene expression mechanisms.


Predicting potential acuities in amblyopes: predicting post-therapy acuity in amblyopes.
Amblyopic patients, or their parents, often want to know the potential for success before committing to treatment. Recent reports have indicated that the pattern visual evoked potential (pVEP) can be used as a predictor of the success of amblyopia therapy. Unfortunately, these studies did not determine if acuity estimates from pVEPs could accurately predict the acuity post-treatment. Furthermore, pVEPs are not always practical to obtain because of the time necessary to acquire the data. Sweep VEPs (sVEP) offer the advantage of rapidly estimating visual acuity in amblyopic patients. In this retrospective study, the relationship between sVEP acuities measured pre-amblyopic therapy and Snellen acuities measured post-amblyopic therapy was determined. Seventeen patients with amblyopia were studied. Monocular sVEP and Snellen acuities were determined pre-amblyopic therapy and Snellen acuities were determined post-amblyopic therapy. An Enfant 4010 computer system was used to produce the stimuli, record the VEPs, and extrapolate the acuity. The stimuli were horizontally oriented, sine wave gratings (11 spatial frequencies from 2 to 24 cpd) with a contrast of 80%, counterphased at 7.5 Hz. Standard VEP recording techniques were employed. Therapy consisted of the full refractive correction and occlusion combined with active vision therapy. The patients demonstrated a significant improvement in pre- to post-amblyopic therapy Snellen acuities (P < 0.00001). The intraclass correlation coefficient (r (i)) between the pre-therapy sVEP acuities and the post-therapy Snellen acuities was 0.73. A paired t-test did not find a significant difference between the two sets of data (P = 0.94). For the amblyopes in this study, the average difference (+/-SD) in the sVEP acuity estimate and the final Snellen visual acuity was +0.002 +/- 0.123 logMAR acuity lines. The results indicate that pre-amblyopic therapy sVEP acuity can be a good predictor of post-amblyopic therapy Snellen acuity.


Integrated analysis of metabolome in a EUS-FNA sample with transcriptome in the TCGA cohort of pancreatic head and body/tail adenocarcinoma.
Metabolome profiles are largely unknown for pancreatic head cancers, in which the predominant anatomical feature is the exosure of bile, pancreatic juice, and duodenal juice. In this research, 30 head and 30 body/tail cytological samples acquired by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of pancreatic adenocarcinoma were delivered for liquid chromatography coupled with mass spectrometry (LC-MS). Transcriptome analysis was performed using the sequencing data from The Cancer Genome Atlas (TCGA) cohort. LC-MS obtained 4,857 features in EUS-FNA cytological samples, and 586 metabolites were certified. Among them, 30 differential metabolites were identified. In the TCGA cohort, 247 differential metabolism genes were selected from 1,583 differential genes. The integrated analysis identified the top three enriched metabolic pathways as follows: branched chain amino acid (BCAA) biosynthesis; glycerophospholipid metabolism; and phenylalanine metabolism. In cell line, BCAA promoted pancreatic cancer proliferation and inhibited Oxaliplatin-induced apoptosis. In conclusion, metabolomic analysis with the EUS-FNA sample is feasible for pancreatic cancer. The integrated analysis can identify key metabolites and enzyme-coded genes between pancreatic head and body/tail adenocarcinoma. Anti-BCAA metabolism therapy may exert promising effect, especially for the body/tail cancer.


Phospholipid metabolism, calcium flux, and the receptor-mediated induction of chemotaxis in rabbit neutrophils.
Rabbit neutrophils were stimulated with the chemotactic peptide fMet-Leu-Phe in the presence of the methyltransferase inhibitors homocysteine (HCYS) and 3-deazaadenosine (3-DZA). HCYS and 3-DZA inhibited chemotaxis, phospholipid methylation, and protein carboxymethylation in a dose-dependent manner. The chemotactic peptide-stimulated release of [14C]arachidonic acid previously incorporated into phospholipid was also partially blocked by the methyltransferase inhibitors. Stimulation by fMet-Leu-Phe or the calcium ionophore A23187 caused release of arachidonic acid but not of previously incorporated [14C]-labeled linoleic, oleic, or stearic acids. Unlike the arachidonic acid release caused by fMet-Leu-Phe, release stimulated by the ionophore could not be inhibited by HCYS and 3-DZA, suggesting that the release was caused by a different mechanism or by stimulating a step after methylation in the pathway from receptor activation to arachidonic acid release. Extracellular calcium was required for arachidonic acid release, and methyltransferase inhibitors were found to partially inhibit chemotactic peptide-stimulated calcium influx. These results suggest that methylation pathways may be associated with the chemotactic peptide receptor stimulation of calcium influx and activation of a phospholipase A2 specific for cleaving arachidonic acid from phospholipids.


Making the connection: a qualitative study of brokerage in Aboriginal health in a metropolitan area of Victoria and a regional area of New South Wales.
Health brokerage is one method being employed by government health agencies in an attempt to improve Aboriginal and Torres Strait Islander people's access to primary healthcare. This qualitative study explores key stakeholders' understanding and acceptance of the health brokerage model, prior to the implementation of brokerage services. Semistructured interviews and focus groups were conducted with key stakeholders. The resulting data was analysed using a grounded theory approach. Qualitative analysis of the interviews and focus groups revealed five major themes. These were: (1) the perceived limitations of brokerage as a service delivery model; (2) the benefits of health brokerage such as increased flexibility; (3) issues relating to patient independence; (4) the necessity for broker independence; and (5) a mistrust of health brokerage and the authority handling the brokerage funds. Since this study was conducted in 2008, ongoing funding for urban brokerage services has been suspended. Although the reasons for this are unclear, our study suggests that barriers to the acceptance of brokerage services by the community may have existed even before such services were implemented, thus highlighting the need for transparency when launching new health initiatives that hope to engage the Aboriginal community.


[A hypothetical model of the biomechanical interaction of the teeth and the abutment tissues of the jaws during masticatory loading of different values].
Biomechanical model "tooth-jaw" in considered. This biomechanical model takes into account local nonhomogeneous mechanical constructions tooth-jaw, its special geometry, physical properties of firm tissues of tooth, periodontium and jaw. Using mathematical methods, determination of supporting jaw tissues depending by computer tomograms was grounded. The system SPLEN-K has calculated tension-deformed condition of dental tissues in area of a group of chew teeth.


Examining Racial Disparities in Historical Change of Mental and Physical Health Across Midlife and Old Age in the United States.
To examine whether racial disparities are narrowing or widening with historical time among U.S. middle-aged and older adults, and test the extent to which educational attainment moderates racial disparities over historical time. Multilevel models were applied to longitudinal data on middle-aged (ages 40-65) and older adults (ages 66 and older) from the Health and Retirement Study. Historical change was indexed as cohort or birth year. The outcomes of focus were depressive symptoms, episodic memory, health conditions, functional limitations, and self-rated health. Results revealed a differential pattern of racial disparities in historical change between midlife and old age. Across midlife and old age, on average, Blacks and Hispanics reported poorer levels of mental and physical health, compared with Whites. In midlife, racial disparities narrowed with historical time; later-born cohorts of Hispanics but not Whites reported fewer depressive symptoms than their earlier-born peers. Likewise, historical improvements in health were stronger among Hispanics and Blacks than Whites. Conversely, in old age, later-born cohorts across race consistently showed historical improvements in each of the outcomes examined. Regarding educational attainment, we observed little consistent evidence that health-promoting effects of educational attainment differ across race and cohort. Examining questions about heterogeneity, results revealed that in midlife and old age there was greater heterogeneity between race across each of the outcomes. Our discussion elaborates on reasons behind the documented racial differences in historical changes among U.S. middle-aged and older adults, and how the protective role of education is changing over time.


Modularly assembled magnetite nanoparticles enhance in vivo targeting for magnetic resonance cancer imaging.
Modularly assembled targeting nanoparticles were synthesized through self-assembly of targeting moieties on surfaces of functional nanoparticles. Specific molecular recognition of nickel nitrilotriacetate on Fe3O4 nanoparticles with hexahistidine tag on RGD4C peptides results in precisely controlled orientation of the targeting peptides. Better selectivity of the self-assembled RGD4C-Fe3O4 nanoparticles targeting oral cancer cells than that achievable through a conventional chemical cross-link strategy was demonstrated by means of atomic absorption spectrometry (AAS). An oral cancer hamster model was applied to reveal specific in vivo targeting and MR molecular imaging contrast in cancer lesions expressing alphavbeta3 integrin. Both AAS and MRI revealed that the self-assembled nanoparticles improved the targeting efficiency and reduced the hepatic uptake as compared with the conventional chemical cross-link particles. We investigated the biosafety, biodistribution, and kinetics of the nanoparticles and found that the nanoparticles were significantly cleared from the liver and kidneys after one week. By recombining the desired targeting moiety and various functional nanoparticles through self-assembly, this new modularly designed platform has the capability of enhancing the efficiency of targeted diagnosis and therapies for a wide spectrum of biomedical applications.


Differential localization of tropomyosin isoforms in cultured nonmuscle cells.
We have previously shown that chicken embryo fibroblast (CEF) cells and human bladder carcinoma (EJ) cells contain multiple isoforms of tropomyosin, identified as a, b, 1, 2, and 3 in CEF cells and 1, 2, 3, 4, and 5 in human EJ cells by one-dimensional SDS-PAGE (Lin, J. J.-C., D. M. Helfman, S. H. Hughes, and C.-S. Chou. 1985. J. Cell Biol. 100: 692-703; and Lin, J. J.-C., S. Yamashiro-Matsumura, and F. Matsumura. 1984. Cancer Cells 1:57-65). Both isoform 3 (TM-3) of CEF and isoforms 4,5 (TM-4,-5) of human EJ cells are the minor isoforms found respectively in normal chicken and human cells. They have a lower apparent molecular mass and show a weaker affinity to actin filaments when compared to the higher molecular mass isoforms. Using individual tropomyosin isoforms immobilized on nitrocellulose papers and sequential absorption of polyclonal antiserum on these papers, we have prepared antibodies specific to CEF TM-3 and to CEF TM-1,-2. In addition, two of our antitropomyosin mAbs, CG beta 6 and CG3, have now been demonstrated by Western blots, immunoprecipitation, and two-dimensional gel analysis to have specificities to human EJ TM-3 and TM-5, respectively. By using these isoform-specific reagents, we are able to compare the intracellular localizations of the lower and higher molecular mass isoforms in both CEF and human EJ cells. We have found that both lower and higher molecular mass isoforms of tropomyosin are localized along stress fibers of cells, as one would expect. However, the lower molecular mass isoforms are also distributed in regions near ruffling membranes. Further evidence for this different localization of different tropomyosin isoforms comes from double-label immunofluorescence microscopy on the same CEF cells with affinity-purified antibody against TM-3, and monoclonal CG beta 6 antibody against TM-a, -b, -1, and -2 of CEF tropomyosin. The presence of the lower molecular mass isoform of tropomyosin in ruffling membranes may indicate a novel way for the nonmuscle cell to control the stability and organization of microfilaments, and to regulate the cell motility.


Supporting children's health needs: an analysis of paid leave policies in 193 countries.
The COVID-19 pandemic has highlighted the extent to which national laws and policies shape public health and economic security. Paid leave policies enable parents to meet children's health needs while maintaining job and income security. These policies matter immensely to children's health every year. Yet, little is known about the extent to which policies exist to support the full range of childhood health needs. Using a novel dataset constructed from legislative text in 193 countries, this study assesses whether laws in place in 2019 are adequate to support meeting children's everyday, serious, and disability-related health needs. Globally, only half of the countries guaranteed working parents access to any paid leave that could be used to meet children's health needs. Only a third addressed everyday health needs, including leave that matters to reducing infectious disease spread. For serious health needs, even when paid leave was available, it was often too short for complex health conditions. Moreover, although all children require parental presence at medical appointments and for serious illness, fewer countries guaranteed paid leave to care for older children than younger. Addressing these gaps is crucial to supporting child health and working families during times of public health crisis and every year.


CCL20 mediates RANK/RANKL-induced epithelial-mesenchymal transition in endometrial cancer cells.
RANK/RANKL facilitates migration/invasion via epithelial-mesenchymal transition (EMT) in certain malignant tumors. The relationship and mechanism between RANK/RANKL and EMT in endometrial cancer (EC) cells, however, remain unclear. In this study, we firstly showed that RANK/RANKL activation was correlated with EC staging and EMT markers in human EC tissue specimen. RANK/RANKL promoted migration/invasion and initiated EMT of EC cell lines. Then, protein chip analysis and enzyme-linked immunosorbent assay (ELISA) revealed that the expression and secretion of chemokine ligand 20 (CCL20) was dramatically enhanced in RANKL-treated RANK over-expressed EC cells. Moreover, the higher level of CCL20 in both serum and tumor tissue was detected in orthotopic transplantation mouse models. Finally, we confirmed that CCL20 contributed to invasion and EMT of RANK over-expressed EC cells. In summary, all data supported the hypothesis that RANK/RANKL elevated the expression and secretion of CCL20 in EC cells, which promoted cancer progression through EMT.


Capture of atmospheric ammonium by grassland canopies.
Air pollution can cause a decline in species through acidification of the habitat. New data suggest that the decline may be due to eutrophication rather than acidification. In Western Europe, eutrophication largely results from atmospheric ammonium deposition. The amount deposited on vegetation is a function of its canopy structure. Deposition on grasslands has been underestimated, and a significant amount of the deposited ammonium appears to be assimilated by the plant canopy. These quantities are sufficient to initiate changes in the competitive relations among the plant species.


All-digital wavefront sensing for structured light beams.
We present a new all-digital technique to extract the wavefront of a structured light beam. Our method employs non-homogeneous polarization optics together with dynamic, digital holograms written to a spatial light modulator to measure the phase relationship between orthogonal polarization states in real-time, thereby accessing the wavefront information. Importantly, we show how this can be applied to measuring the wavefront of propagating light fields, over extended distances, without any moving components. We illustrate the versatility of the tool by measuring propagating optical vortices, Bessel, Airy and speckle fields. The comparison of the extracted and programmed wavefronts yields excellent agreement.


Using disease-related and demographic variables to form cancer-distress risk groups.
The use of disease-related (i.e., stage, phase, perceived health) and demographic (i.e., age, education, income) variables to identify subgroups of cancer patients and survivors manifesting divergent risk for psychosocial adjustment problems was assessed. Clustering procedures distinguished three clusters across two subsamples. In each subsample, low-risk participants had a low stage, a later phase, high perceived health, an older age, and a high education and income; moderate-risk participants had a low stage, a later phase, high perceived health, a greater age, and a low education and income; and high-risk individuals had high stage, an earlier phase, low perceived health, an average age, and a low education and income. Mean difference analyses showed that low-risk participants had higher psychosocial adjustment than high- and moderate-risk participants. High-risk participants had lower psychosocial adjustment than moderate-risk participants. The risk for psychosocial adjustment problems may be influenced by disease-related and demographic variables, and implications for the targeting of interventions are discussed.


Corticosteroids for the treatment of Kawasaki disease in children.
Kawasaki disease (KD), or mucocutaneous syndrome, is the leading cause of childhood-acquired heart disease in the developed world. There is much controversy on how best to treat children with KD and in particular who may benefit from additional treatment beyond the standard intravenous immunoglobulin (IVIG) and aspirin, such as the addition of corticosteroids. To assess the impact of corticosteroid use on the incidence of coronary artery abnormalities in KD as either first-line or second-line treatment. Corticosteroids may be given alone or in conjunction with other accepted KD treatments. Secondary objectives include the effect of steroids on mortality, the time taken for laboratory parameters to normalise, the duration of acute symptoms (such as fever), the long-term impact of steroid use and evaluating their safety in KD and their efficacy in relevant population subgroups. The Cochrane Vascular Information Specialist searched Cochrane Vascular's Specialised Register (25 November 2016) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 10) in the Cochrane Library (searched 25 November 2016). Trial registries were also searched for details of ongoing or unpublished studies. We selected randomised trials involving children with all severities of KD who were treated with corticosteroids, including different types of corticosteroid and different durations of treatment. MJS and GMC independently selected studies, assessed evidence quality and extracted data. This process was overseen by AJW. Seven trials consisting of 922 participants were included in this analysis. Trials ranged from 32 to 242 participants. On pooled analysis, corticosteroids reduced the subsequent occurrence of coronary artery abnormalities (odds ratio (OR) 0.29, 95% confidence interval (CI) 0.18 to 0.46; 907 participants; 7 studies; I² = 55%) without resultant serious adverse events (no events, 737 participants) and mortality (no events, 915 participants). In addition, corticosteroids reduced the duration of fever (mean difference (MD) -1.65 days, 95% CI -3.31 to 0.00; 210 participants; 2 studies; I² = 88%), time for laboratory parameters (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) to normalise (MD -2.80 days, 95% CI -4.38 to -1.22; 178 participants; 1 study) and length of hospital stay (MD -1.41 days, 95% CI -2.36 to -0.46; 39 participants; 1 study). No studies detailed outcomes beyond 24 weeks. Subgroup analysis showed some potential groups that may benefit more than others; however, further randomised controlled trials are required before this can be the basis for clinical action.Evidence quality was graded according to the GRADE system. Evidence was considered high quality for the incidence of serious adverse events, mortality and time for laboratory parameters to normalise. Evidence was considered moderate for the incidence of coronary artery abnormalities due to potential inconsistencies in data geography and patient benefits according to grouping. Evidence was moderate for duration of clinical symptoms (fever, rash) due to potential subjectivity in measurement. Evidence was moderate for length of hospital stay as only one study recorded this outcome. This means that we are reasonably confident that the true effect is close to that estimated in this work. Moderate-quality evidence shows that use of steroids in the acute phase of KD can be associated with improved coronary artery abnormalities, shorter duration of hospital stay and a decreased duration of clinical symptoms. High-quality evidence shows reduced inflammatory marker levels. There were insufficient data available regarding incidence of adverse effects attributable to steroids, mortality and long-term (> 1 year) coronary morbidity. Certain groups, including those based in Asia, those with higher risk scores, and those receiving longer steroid treatment may have greater benefit from steroid use, especially with decreasing rates of heart problems, but more tests are needed to answer these questions. Evidence presented in this study suggests that treatment with a long course of steroids should be considered for all children diagnosed with KD until further studies are performed.


Pea legumin overexpressed in wheat endosperm assembles into an ordered paracrystalline matrix.
Legumin, a major component of pea seed storage vacuoles, is synthesized by a number of paralogous genes. The polypeptides are cleaved posttranslationally and can form mixed hexamers. This heterogeneity hampers structural studies, based on the production of hexamer crystals in vitro. To study a single type of homogenous legumin we produced pea legumin A in transgenic wheat (Triticum aestivum) endosperm where prolamins are predominant and only small amounts of globulins accumulate in separate inclusions. We demonstrated that the legumin precursor was cleaved posttranslationally and we confirmed assembly into 11S hexamers. Legumin was deposited within specific regions of the inclusion bodies. Angular legumin crystals extended from the inclusion bodies into the vacuole, correlating with the high legumin content. This suggests that the high-level production of a single type of legumin polypeptide resulted in the spontaneous formation of crystals in vivo. The use of a heterologous cereal system such as wheat endosperm to produce, isolate, and recrystallize homogenous 11S legume globulins offers exciting possibilities for structural analysis and characterization of these important seed storage proteins.


Assessment Trends Among Neuropsychologists Conducting Sport-Related Concussion Evaluations.
Neuropsychologists regularly conduct sport-related concussion (SRC) evaluations, although research has not tracked these assessment practices. As part of a survey of neuropsychological test usage, we analyzed data from 215 neuropsychologists who conduct SRC evaluations. Only 15% reported conducting baseline assessments of athletes as part of a sports program and 92% evaluate athletes' post-concussion without baseline data. The majority of respondents use a full battery, considered the most reliable approach for assessing concussion symptoms in athletes. Only 6% use computerized tests exclusively (>50% ImPACT). We discuss the implications of these results and address challenges faced by neuropsychologists who perform SRC evaluations.


An evaluation of a new approach to the regeneration of Helichrysum italicum (Roth) G. Don, and the molecular characterization of the variation among sets of differently derived regenerants.
A protocol for the induction of regeneration from leaves of Helichrysum italicum was established. Calli were found to form on the basal medium only when it was supplemented with thidiazuron (TDZ) alone or in combination with naphthalene acetic acid (NAA), with a percentage ranking of at least 80%. The hormone-free medium showed the highest percentage of shoot regeneration (62%) even though no callus formed. AFLP markers were employed to verify tissue culture-induced variation in the regenerated plantlets obtained by direct shoot regeneration or the indirect shoot regeneration process (callus formation). Seven out of the eleven AFLP primer pairs yielded polymorphic patterns. The average number of fragments per primer pair was 64.1. Singletons were represented by 12 (2.7%) fragments. Student's T-test was performed both on the average number of shared fragments and on the nucleotide diversity, and no significant statistical difference was observed between the two regeneration treatments.


Varying efficacy of Helicobacter pylori eradication regimens: cost effectiveness study using a decision analysis model.
To determine how small differences in the efficacy and cost of two antibiotic regimens to eradicate Helicobacter pylori can affect the overall cost effectiveness of H pylori eradication in duodenal ulcer disease. A decision analysis to examine the cost effectiveness of eight H pylori eradication strategies for duodenal ulcer disease with and without 13C-urea breath testing to confirm eradication. Cumulative direct treatment costs per 100 patients with duodenal ulcer disease who were positive for H pylori. In model 1 the strategy of omeprazole, clarithromycin, and metronidazole alone was the most cost effective of the four strategies assessed. The addition of the 13C-urea breath test and a second course of omeprazole, clarithromycin, and metronidazole achieved the highest eradication rate (97%) but was the most expensive (62.63 pounds per patient). The cost of each additional effective eradication was 589.00 pounds (incremental cost per case) when compared with the cost of treating once only with omeprazole, clarithromycin, and metronidazole; equivalent to the cost of a patient receiving ranitidine for duodenal ulcer relapse for more than 15 years. Eradication strategies of omeprazole, amoxycillin, and metronidazole were less cost effective than omeprazole, clarithromycin, and metronidazole alone. In model 2 the addition of the 13C-urea breath test after treatment, and maintenance treatment, increased the cost of all the strategies and reduced the cost advantage of omeprazole, clarithromycin, and metronidazole alone. Small differences in efficacy can influence the comparative cost effectiveness of strategies for eradicating H pylori. Of the strategies tested the most cost effective (omeprazole, clarithromycin, and metronidazole alone) was neither the least expensive (omeprazole, amoxycillin, and metronidazole alone) nor the most effective (omeprazole, clarithromycin, and metronidazole with further treatment for patients found positive for H pylori on 13C-urea breath testing). Cost effectiveness should be an important part of choosing an eradication strategy for H pylori.


Scale matters: the impact of organic farming on biodiversity at different spatial scales.
There is increasing recognition that ecosystems and their services need to be managed in the face of environmental change. However, there is little consensus as to the optimum scale for management. This is particularly acute in the agricultural environment given the level of public investment in agri-environment schemes (AES). Using a novel multiscale hierarchical sampling design, we assess the effect of land use at multiple spatial scales (from location-within-field to regions) on farmland biodiversity. We show that on-farm biodiversity components depend on farming practices (organic vs. conventional) at farm and landscape scales, but this strongly interacts with fine- and coarse-scale variables. Different taxa respond to agricultural practice at different spatial scales and often at multiple spatial scales. Hence, AES need to target multiple spatial scales to maximize effectiveness. Novel policy levers may be needed to encourage multiple land managers within a landscape to adopt schemes that create landscape-level benefits.


pH homeostasis in the frog retina: the role of Na+:HCO3- co-transport in the retinal pigment epithelium.
Transport of acid/base equivalents across the isolated frog retinal pigment epithelium (RPE) was studied by means of pH selective microelectrodes. Abrupt changes in retinal extracellular pH, from 7.40 to values between 6.66 and 7.66, were found to cause rapid changes in both intracellular pH and choroidal extracellular pH. The initial rates of these changes were reduced by more than 60%, when the cellular Na+:HCO3- co-transport system was inhibited by Na+ removal, or by administration of 1 mM SITS. It is concluded that RPE transcellular HCO3- transport changed in response to changes in retinal extracellular pH. If present in vivo these changes in RPE HCO3- transport would tend to stabilize retinal extracellular pH. It is suggested that cellular Na+:HCO3- cotransport plays a significant role for the retinal pH homeostasis.


Genetic Modification of Tumor-Infiltrating Lymphocytes, Peripheral T Cells, and T-Cell Model Cell Lines.
Genetic modification of tumor-infiltrating lymphocytes (TILs) or circulating T cells has become an important avenue in cancer therapy. Here we describe a comprehensive method for establishing and expanding TIL cultures and genetically modifying them with a gene of interest (GOI) via retroviral transduction or mRNA transfection. The method includes all the important steps starting with TIL extraction from tumors through to the maintenance of the genetically modified TILs. The protocol includes instructions for retroviral transduction and mRNA transfection of circulating T cells or T-cell lines. The GOIs most commonly introduced into the target cells are chimeric antigen receptors (CARs); genetic adjuvants, such as membrane-bound interleukins; and antitumor T-cell receptors (TCRs).


[Plasmid vectors of "insertion inactivation" of the trimethoprim resistance marker].
We demonstrate the possibility of using the T4 phage frd gene as an insertion inactivation marker within pBR322, in plasmids with changing copy number and expression of foreign genes under control. The structural part of the frd genes contains unique recognition sites for EcoRI and SalI endonucleases. Transformants with recombinant plasmids carrying the frd gene grow on media with up to 500 mkg/ml trimethoprim, whatever the gene dosage.


Multifunctional Cationic Hyperbranched Polyaminoglycosides that Target Multiple Mediators for Severe Abdominal Trauma Management.
Trauma and its associated complications, including dysregulated inflammatory responses, severe infection, and disseminated intravascular coagulation (DIC), continue to pose lethal threats worldwide. Following injury, cell-free nucleic acids (cfNAs), categorized as damage-associated molecular patterns (DAMPs), are released from dying or dead cells, triggering local and systemic inflammatory responses and coagulation abnormalities that worsen disease progression. Harnessing cfNA scavenging strategies with biomaterials has emerged as a promising approach for treating posttrauma systemic inflammation. In this study, the effectiveness of cationic hyperbranched polyaminoglycosides derived from tobramycin (HPT) and disulfide-included HPT (ss-HPT) in scavenging cfNAs to mitigate posttrauma inflammation and hypercoagulation is investigated. Both cationic polymers demonstrate the ability to suppress DAMP-induced toll-like receptor (TLR) activation, inflammatory cytokine secretion, and hypercoagulation by efficiently scavenging cfNAs. Additionally, HPT and ss-HPT exhibit potent antibacterial efficacy attributed to the presence of tobramycin in their chemical composition. Furthermore, HPT and ss-HPT exhibit favorable modulatory effects on inflammation and therapeutic outcomes in a cecal ligation puncture (CLP) mouse abdominal trauma model. Notably, in vivo studies reveal that ss-HPT displayed high accumulation and retention in injured organs of traumatized mice while maintaining a higher biodegradation rate in healthy mice, contrasting with findings for HPT. Thus, functionalized ss-HPT, a bioreducible polyaminoglycoside, holds promise as an effective option to enhance therapeutic outcomes for trauma patients by alleviating posttrauma inflammation and coagulation complications.


Efficient Carrier Multiplication in Colloidal Silicon Nanorods.
Auger recombination lifetimes, absorption cross sections, and the quantum yields of carrier multiplication (CM), or multiexciton generation (MEG), were determined for solvent-dispersed silicon (Si) nanorods using transient absorption spectroscopy (TAS). Nanorods with an average diameter of 7.5 nm and aspect ratios of 6.1, 19.3, and 33.2 were examined. Colloidal Si nanocrystals of similar diameters were also studied for comparison. The nanocrystals and nanorods were passivated with organic ligands by hydrosilylation to prevent surface oxidation and limit the effects of surface trapping of photoexcited carriers. All samples used in the study exhibited relatively efficient photoluminescence. The Auger lifetimes increased with nanorod length, and the nanorods exhibited higher CM quantum yield and efficiency than the nanocrystals with a similar band gap energy Eg. Beyond a critical length, the CM quantum yield decreases. Nanorods with the aspect ratio of 19.3 had the highest CM quantum yield of 1.6 ± 0.2 at 2.9Eg, which corresponded to a multiexciton yield that was twice as high as observed for the spherical nanocrystals.


Impaired letter-string processing in developmental dyslexia: what visual-to-phonology code mapping disorder?
Poor parallel letter-string processing in developmental dyslexia was taken as evidence of poor visual attention (VA) span, that is, a limitation of visual attentional resources that affects multi-character processing. However, the use of letter stimuli in oral report tasks was challenged on its capacity to highlight a VA span disorder. In particular, report of poor letter/digit-string processing but preserved symbol-string processing was viewed as evidence of poor visual-to-phonology code mapping, in line with the phonological theory of developmental dyslexia. We assessed here the visual-to-phonological-code mapping disorder hypothesis. In Experiment 1, letter-string, digit-string and colour-string processing was assessed to disentangle a phonological versus visual familiarity account of the letter/digit versus symbol dissociation. Against a visual-to-phonological-code mapping disorder but in support of a familiarity account, results showed poor letter/digit-string processing but preserved colour-string processing in dyslexic children. In Experiment 2, two tasks of letter-string report were used, one of which was performed simultaneously to a high-taxing phonological task. Results show that dyslexic children are similarly impaired in letter-string report whether a concurrent phonological task is simultaneously performed or not. Taken together, these results provide strong evidence against a phonological account of poor letter-string processing in developmental dyslexia.


Patterns of lipid changes among type 2 diabetes patients in Sudan.
This study investigated the patterns and determinants of lipid disorders among a group of 250 type 2 adult diabetic patients and 60 age- and sex-matched healthy controls in Sudan. Demographic and clinical data, body mass index and waist circumference, and fasting blood samples were taken to estimate the glucose and lipid profile. The mean duration of diabetes was 9.4 years and 46.0% of patients had poor glycaemic control. Compared to controls we detected a statistically significant increase in triglycerides level and a decrease in HDL-C levels. Other lipid values showed a slight increase compared to controls. There was a statistically significant association of triglycerides and HDL-C with increasing age, female sex, obesity, physical inactivity and poor glycaemic control of diabetes.


A Dairy-Derived Ghrelinergic Hydrolysate Modulates Food Intake In Vivo.
Recent times have seen an increasing move towards harnessing the health-promoting benefits of food and dietary constituents while providing scientific evidence to substantiate their claims. In particular, the potential for bioactive protein hydrolysates and peptides to enhance health in conjunction with conventional pharmaceutical therapy is being investigated. Dairy-derived proteins have been shown to contain bioactive peptide sequences with various purported health benefits, with effects ranging from the digestive system to cardiovascular circulation, the immune system and the central nervous system. Interestingly, the ability of dairy proteins to modulate metabolism and appetite has recently been reported. The ghrelin receptor (GHSR-1a) is a G-protein coupled receptor which plays a key role in the regulation of food intake. Pharmacological manipulation of the growth hormone secretagogue receptor-type 1a (GHSR-1a) receptor has therefore received a lot of attention as a strategy to combat disorders of appetite and body weight, including age-related malnutrition and the progressive muscle wasting syndrome known as cachexia. In this study, a milk protein-derivative is shown to increase GHSR-1a-mediated intracellular calcium signalling in a concentration-dependent manner in vitro. Significant increases in calcium mobilisation were also observed in a cultured neuronal cell line heterologously expressing the GHS-R1a. In addition, both additive and synergistic effects were observed following co-exposure of GHSR-1a to both the hydrolysate and ghrelin. Subsequent in vivo studies monitored standard chow intake in healthy male and female Sprague-Dawley rats after dosing with the casein hydrolysate (CasHyd). Furthermore, the provision of gastro-protected oral delivery to the bioactive in vivo may aid in the progression of in vitro efficacy to in vivo functionality. In summary, this study reports a ghrelin-stimulating bioactive peptide mixture (CasHyd) with potent effects in vitro. It also provides novel and valuable translational data supporting the potential role of CasHyd as an appetite-enhancing bioactive. Further mechanistic studies are required in order to confirm efficacy as a ghrelinergic bioactive in susceptible population groups.


Measurement of cerebrospinal fluid oxygen partial pressure in humans using MRI.
Fluid-attenuated inversion recovery (FLAIR) images obtained during the administration of supplemental oxygen demonstrate a hyperintense signal within the cerebrospinal fluid (CSF) that is likely caused by T1 changes induced by paramagnetic molecular oxygen. Previous studies demonstrated a linear relationship between the longitudinal relaxation rate (R1 = 1/T1) and oxygen content, which permits quantification of the CSF oxygen partial pressure (P(csf)O2). In the current study, CSF T1 was measured at 1.5 T in the lateral ventricles, third ventricle, cortical sulci, and basilar cisterns of eight normal subjects breathing room air or 100% oxygen. Phantom studies performed with artificial CSF enabled absolute P(csf)O2 quantitation. Regional P(csf)O2 differences on room air were observed, from 65 +/- 27 mmHg in the basilar cisterns to 130 +/- 49 mmHg in the third ventricle. During 100% oxygen, P(csf)O2 increases of 155 +/- 45 and 124 +/- 34 mmHg were measured in the basilar cisterns and cortical sulci, respectively, with no change observed in the lateral or third ventricles. P(csf)O2 measurements in humans breathing room air or 100% oxygen using a T1 method are comparable to results from invasive human and animal studies. Similar approaches could be applied to noninvasively monitor oxygenation in many acellular, low-protein body fluids.


Familial haemophagocytic reticulosis. Report of 2 cases in sibs.
Two cases of familial haemophagocytic reticulosis occurring in sibs are described. The disease is characterised by a widespread proliferation of histocytes showing haemophagocytosis and it usually manifests clinically with haematological abnormalities. The initial presentation may be that of a meningo-encephalitic illness, the result of a lymphohistiocytic infiltration of the meninges and cerebral tissues. The clinical course and pathological features are described and the differential diagnosis is discussed.


[The postoperative pancreatitis after the pancreatic surgery].
The results of 302 operations on the pancreas were analyzed: of them 107 were pancreatoduodenal resections; 67 were distal resections of the pancreas; 74 were various resections of the head of the pancreas and middle resections and 54 other operations. The postoperative pancreatitis was registered in 178 patients. The preventive use of the octreotide intraoperatively and in early postoperative period showed no influence on the frequency and severity of the postoperative pancreatitis. The ultrasound was the optimal screening diagnostig method, whereas the computed tomography was the best in pancreonecrosis diagnostics and the volume of the pancreatic tissue damaged. Of 178 patients with the postoperative pancreatitis 17 died, the lethality rate was 9.5%.


Failing the future: three unsuccessful attempts to replicate Bem's 'retroactive facilitation of recall' effect.
Nine recently reported parapsychological experiments appear to support the existence of precognition. We describe three pre-registered independent attempts to exactly replicate one of these experiments, 'retroactive facilitation of recall', which examines whether performance on a memory test can be influenced by a post-test exercise. All three replication attempts failed to produce significant effects (combined n = 150; combined p = .83, one-tailed) and thus do not support the existence of psychic ability.


Reversible solvatomagnetic effect in novel tetranuclear cubane-type Ni4 complexes and magnetostructural correlations for the [Ni4(μ3-O)4] core.
A new family of tetranuclear nickel cube complexes [Ni(4)L(4)(solv)(4)] (1, solv = MeOH; 2, solv = H(2)O; H(2)L = pyrazole-based tridentate {ONO} ligand) has been studied in detail, in particular by X-ray diffraction and superconducting quantum interference device (SQUID) magnetometry. Different solvates 1·H(2)O, 2·4C(3)H(6)O, 2·CH(2)Cl(2), and 2·H(2)O were obtained in crystalline form. Only small structural variations were found for the Ni-O-Ni angles of the [Ni(4)O(4)] cores of those compounds, but these slight variations have dramatic consequences for the magnetic properties. [Ni(4)L(4)(MeOH)(4)]·H(2)O (1·H(2)O) and [Ni(4)L(4)(H(2)O)(4)]·H(2)O (2·H(2)O) can be reversibly interconverted in the solid state by exposure to the respective solvent, MeOH or H(2)O, and this goes along with a switching of the spin ground state from magnetic (S(T) = 4) to diamagnetic (S(T) = 0). Likewise the (irreversible) loss of lattice solvent in [Ni(4)L(4)(H(2)O)(4)]·4C(3)H(6)O (2·4C(3)H(6)O) to give 2·2C(3)H(6)O changes the ground state from S(T) = 4 to S(T) = 0. In view of these dramatic solvatomagnetic effects for the present [Ni(4)L(4)(solv)(4)] complexes, which occur upon extrusion of lattice solvent or facile exchange of coordinated solvent molecules while keeping the robust [Ni(4)O(4)] core intact, a note of care is issued: whenever magnetic data are obtained for powdered material or for crystals that easily loose lattice solvent molecules, the magnetic properties may not necessarily reflect the situation observed in the corresponding single crystal diffraction study. Finally, a thorough analysis of the present series of complexes as well as other {Ni(4)(μ(3)-OR)(4)} cubes reported in the literature confirms that a correlation between the (Ni-O-Ni)(av) bond angle and J in [Ni(4)O(4)] cubane complexes does indeed exist.


Chatbot Artificial Intelligence for Genetic Cancer Risk Assessment and Counseling: A Systematic Review and Meta-Analysis.
Most individuals with a hereditary cancer syndrome are unaware of their genetic status to underutilization of hereditary cancer risk assessment. Chatbots, or programs that use artificial intelligence to simulate conversation, have emerged as a promising tool in health care and, more recently, as a potential tool for genetic cancer risk assessment and counseling. Here, we evaluated the existing literature on the use of chatbots in genetic cancer risk assessment and counseling. A systematic review was conducted using key electronic databases to identify studies which use chatbots for genetic cancer risk assessment and counseling. Eligible studies were further subjected to meta-analysis. Seven studies met inclusion criteria, evaluating five distinct chatbots. Three studies evaluated a chatbot that could perform genetic cancer risk assessment, one study evaluated a chatbot that offered patient counseling, and three studies included both functions. The pooled estimated completion rate for the genetic cancer risk assessment was 36.7% (95% CI, 14.8 to 65.9). Two studies included comprehensive patient characteristics, and none involved a comparison group. Chatbots varied as to the involvement of a health care provider in the process of risk assessment and counseling. Chatbots have been used to streamline genetic cancer risk assessment and counseling and hold promise for reducing barriers to genetic services. Data regarding user and nonuser characteristics are lacking, as are data regarding comparative effectiveness to usual care. Future research may consider the impact of chatbots on equitable access to genetic services.


De novo assembly and annotation of the retinal transcriptome for the Nile grass rat (Arvicanthis ansorgei).
Cone photoreceptors are required for color vision and high acuity vision, and they die in a variety of retinal degenerations, leading to irreversible vision loss and reduced quality of life. To date, there are no approved therapies that promote the health and survival of cones. The development of novel treatments targeting cones has been challenging and impeded, in part, by the limitations inherent in using common rodent model organisms, which are nocturnal and rod-dominant, to study cone biology. The African Nile grass rat (Arvicanthis ansorgei), a diurnal animal whose photoreceptor population is more than 30% cones, offers significant potential as a model organism for the study of cone development, biology, and degeneration. However, a significant limitation in using the A. ansorgei retina for molecular studies is that A. ansorgei does not have a sequenced genome or transcriptome. Here we present the first de novo assembled and functionally annotated transcriptome for A. ansorgei. We performed RNA sequencing for A. ansorgei whole retina to a depth of 321 million pairs of reads and assembled 400,584 Trinity transcripts. Transcriptome-wide analyses and annotations suggest that our data set confers nearly full length coverage for the majority of retinal transcripts. Our high quality annotated transcriptome is publicly available, and we hope it will facilitate wider usage of A. ansorgei as a model organism for molecular studies of cone biology and retinal degeneration.


SARS-CoV-2 Omicron spike mediated immune escape and tropism shift.
The SARS-CoV-2 Omicron BA.1 variant emerged in late 2021 and is characterised by multiple spike mutations across all spike domains. Here we show that Omicron BA.1 has higher affinity for ACE2 compared to Delta, and confers very significant evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralising antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralisation. Importantly, antiviral drugs remdesevir and molnupiravir retain efficacy against Omicron BA.1. We found that in human nasal epithelial 3D cultures replication was similar for both Omicron and Delta. However, in lower airway organoids, Calu-3 lung cells and gut adenocarcinoma cell lines live Omicron virus demonstrated significantly lower replication in comparison to Delta. We noted that despite presence of mutations predicted to favour spike S1/S2 cleavage, the spike protein is less efficiently cleaved in live Omicron virions compared to Delta virions. We mapped the replication differences between the variants to entry efficiency using spike pseudotyped virus (PV) entry assays. The defect for Omicron PV in specific cell types correlated with higher cellular RNA expression of TMPRSS2, and accordingly knock down of TMPRSS2 impacted Delta entry to a greater extent as compared to Omicron. Furthermore, drug inhibitors targeting specific entry pathways demonstrated that the Omicron spike inefficiently utilises the cellular protease TMPRSS2 that mediates cell entry via plasma membrane fusion. Instead, we demonstrate that Omicron spike has greater dependency on cell entry via the endocytic pathway requiring the activity of endosomal cathepsins to cleave spike. Consistent with suboptimal S1/S2 cleavage and inability to utilise TMPRSS2, syncytium formation by the Omicron spike was dramatically impaired compared to the Delta spike. Overall, Omicron appears to have gained significant evasion from neutralising antibodies whilst maintaining sensitivity to antiviral drugs targeting the polymerase. Omicron has shifted cellular tropism away from TMPRSS2 expressing cells that are enriched in cells found in the lower respiratory and GI tracts, with implications for altered pathogenesis.


The Impact of Lifestyle, Diet and Physical Activity on Epigenetic Changes in the Offspring-A Systematic Review.
This systematic review examines the association between maternal lifestyle, diet and physical activity, and epigenetic changes in the offspring. A literature search was conducted using multiple science databases: PubMed, Embase and Cochrane Library, on 10 March 2021. RCT and Cohort studies in English or Scandinavian languages were included. Exposure variables included diet, lifestyle, meal patterns or physical activity. Studies using dietary supplements as exposure variables were excluded. Outcome variables included were DNA methylation, microRNA or histone changes in placenta, cord blood or offspring. Two independent authors screened, read and extracted data from the included papers. The Cochrane risk-of-bias tool for randomized trials (RoB2) and The Critical Appraisal Skills Program (CASP) Cohort Study Checklist were used to assess risk of bias in the included studies. A qualitative approach was employed due to heterogeneity of exposures and results of the studies. 16 studies and 3617 participants were included in the final analysis. The exposure variables included physical activity, carbohydrate, low glycemic index diet, added sugar, fat, Mediterranean diet and pro-inflammatory diet. The outcome variables identified were differences in DNA methylation and microRNA. Most studies described epigenetic changes in either placenta or cord blood. Genes reported to be methylated were GR, HSD2, IGF-2, PLAG1, MEG-3, H19 and RXRA. However, not all studies found epigenetic changes strong enough to pass multiple testing, and the study quality varied. Despite the variable quality of the included studies, the results in this review suggest that there may be an association between the mother's lifestyle, diet and level of physical activity during pregnancy and epigenetic changes in the offspring.


Experimental and theoretical investigation of laser-induced plasma of a titanium target.
We present a theoretical approach to interpreting optical emission spectroscopy measurements for nonequilibrium conditions. In this approach both the fluid dynamics and the kinetics of laser-induced plasma are taken into account, and the results obtained by the numerical model are applied to the spectroscopic observation of the plasma induced by the interaction between a KrF laser and a metallic Ti target. We have generalized the theoretical method to calculate the initial conditions for the plume expansion that show the best agreement with experimental results.


Clarithromycin, QTc interval prolongation and torsades de pointes: the need to study case reports.
The manufacturers of clarithromycin sought a drug similar in efficacy to erythromycin but with a superior side-effect profile. They generally achieved this outcome, but postmarketing findings identified a series of reports linking clarithromycin to QTc interval prolongation and torsades de pointes (TdP) ultimately leading to a Black Box Warning. We sought to clarify risk factors associated with TdP among case reports of patients receiving clarithromycin linked to QTc interval prolongation and TdP. In a detailed literature search, we found 15 women, five men, and one boy meeting our search criteria. Among the 17 adults with reported clarithromycin dose and concurrent QTc interval measurement, we found no statistically significant relationship between clarithromycin dose and QTc interval duration. This did not change for the adults who developed TdP. Among adults, major risk factors were female sex (15), old age (11) and heart disease (17). A total of eight adult subjects had all three major risk factors and 14 of the 20 adults had at least two major risk factors. All adult subjects had at least two risk factors besides clarithromycin. A total of four of the 20 adults received cisapride and three received disopyramide. Three adults were considered to suffer from some aspect of the congenital long QT syndrome. We believe that the risk factor description for this drug should be refined to emphasize the major risk factors of (1) female sex, (2) old age and (3) heart disease.


Successful paclitaxel-based chemotherapy for an alpha-fetoprotein-producing gastric cancer patient with multiple liver metastases.
Alpha-fetoprotein (AFP)-producing gastric cancer is known to frequently cause multiple liver metastases and to have an extremely poor prognosis. A 64-year-old Japanese man admitted to our hospital was diagnosed with gastric cancer with liver metastases. He underwent a total gastrectomy with splenectomy, and pathological stage IV disease according to the classification proposed by the Japanese Gastric Cancer Association was assigned. The histological diagnosis was poorly differentiated adenocarcinoma, and tumor production of AFP was confirmed by immunohistochemical staining. Following surgery, the patient received combination chemotherapy consisting of TS-1 and paclitaxel. Initially, AFP levels decreased dramatically and computed tomography (CT) revealed regression of liver metastases. However, multiple new liver metastases appeared and serum AFP levels increased after 5 months. A regimen of 5-FU plus paclitaxel followed by paclitaxel monotherapy was used next. Serum AFP levels once again decreased and CT showed regression or disappearance of liver metastases. The patient currently has a very good quality of life, and is receiving weekly paclitaxel monotherapy as an outpatient. No progression of liver metastases has been observed to date. We consider this rare case to have significant value with respect to treatment of AFP-producing gastric cancer with multiple liver metastases, and propose that combining surgery with chemotherapeutic agents such as paclitaxel may lead to a better prognosis in such cases.


Image-guided resection of cerebral cavernous malformations.
To evaluate retrospectively the effectiveness of image-guided navigation techniques in the management of cerebral CMs. Between July 1997 and January 2001, 44 patients underwent image-guided resection of cerebral CMs. To counteract brain shift, a small silicon catheter was implanted as a guide in the case of deep-seated lesions (except in the case of brain stem CMs) and before excision of multiple lesions. A total of 27 men and 17 women with a mean age of 35 years underwent surgical procedures (5 patients had multiple lesions). The lesions were located in the frontal (n = 14), lobe temporal lobe (n = 12), parietal lobe (n = 6), cerebellum (n = 6), thalamus (n = 5), pons (n = 5), and orbital region (n = 1). Under the guidance of a StealthStation navigator, total removal of the lesions was achieved in all patients. Follow-up revealed marked improvement of preoperative symptoms in 26 patients and no additional deficits in 13 patients. Five patients suffered from additional neurological deficits, but two of them gradually improved during the follow-up period. With the assistance of an image-guided surgical system, functional areas can be effectively avoided and surgical injury can be decreased. This system is well suited for accurate localization and safe resection of small, deep-seated CMs.


CircosVCF: circos visualization of whole-genome sequence variations stored in VCF files.
Visualization of whole-genomic variations in a meaningful manner assists researchers in gaining new insights into the underlying data, especially when it comes in the context of whole genome comparisons. CircosVCF is a web based visualization tool for genome-wide variant data described in VCF files, using circos plots. The user friendly interface of CircosVCF supports an interactive design of the circles in the plot, and the integration of additional information such as experimental data or annotations. The provided visualization capabilities give a broad overview of the genomic relationships between genomes, and allow identification of specific meaningful SNPs regions. CircosVCF was implemented in JavaScript and is available at http://www.ariel.ac.il/research/fbl/software. email@example.com. Supplementary data are available at Bioinformatics online.


Hyperbolic exciton polaritons in a van der Waals magnet.
Exciton polaritons are quasiparticles of photons coupled strongly to bound electron-hole pairs, manifesting as an anti-crossing light dispersion near an exciton resonance. Highly anisotropic semiconductors with opposite-signed permittivities along different crystal axes are predicted to host exotic modes inside the anti-crossing called hyperbolic exciton polaritons (HEPs), which confine light subdiffractionally with enhanced density of states. Here, we show observational evidence of steady-state HEPs in the van der Waals magnet chromium sulfide bromide (CrSBr) using a cryogenic near-infrared near-field microscope. At low temperatures, in the magnetically-ordered state, anisotropic exciton resonances sharpen, driving the permittivity negative along one crystal axis and enabling HEP propagation. We characterize HEP momentum and losses in CrSBr, also demonstrating coupling to excitonic sidebands and enhancement by magnetic order: which boosts exciton spectral weight via wavefunction delocalization. Our findings open new pathways to nanoscale manipulation of excitons and light, including routes to magnetic, nonlocal, and quantum polaritonics.


[Epidemiology of hematogenous infections due to Candida spp].
Candida spp is associated to almost 80% of all nosocomial fungal infections and is considered a major cause of blood stream infections. Candida spp is the fourth most common cause of blood stream infections in the United States, where this agent is responsible for 8% of all invasive infections documented in this site. At the present, non-albicans species are related to at least 50% of all invasive infections due to Candida spp and they present differences in terms of clinical outcome as well as susceptibility to antifungal drugs. The crude mortality rate of candidemia is between 40 and 60% which makes this infection an important challenge for all clinicians from tertiary care hospitals of diverse different countries.


From pulmonary susceptible tuberculosis to extensively drug resistant tuberculosis: An interesting case report of a young Indian girl.
Tuberculosis is one of the top ten causes of death and the leading cause from a single infectious agent. Drug-resistant Tuberculosis continues to be a public health crisis. Urgent action is required to improve the coverage and quality of diagnosis, treatment and care for people with drug-resistant Tuberculosis. Patients with pulmonary Tuberculosis can spread the disease by coughing, sneezing, or simply talking. For that reason, it is important to diagnosis Tuberculosis in order to start treatment as soon as possible. In the present manuscript we present the case of a 25-year-old Indian HIV-negative female, no comorbidity, with a history of drug susceptible tuberculosis diagnosed in 2015 which advanced in extensively drug-resistant tuberculosis after two years of treatment. This case report highlights the risk of mismanagement of patient affected by Tuberculosis and the consequences related which could harm the patient's health.


Action of MDMA (ecstasy) and its metabolites on arginine vasopressin release.
3,4-Methylenedioxymethamphetamine (MDMA) has been reported to cause hyponatraemia, which appears to result from inappropriate secretion of the antidiuretic hormone arginine vasopressin (AVP). After administration of a low dose of (R,S)-MDMA (40 mg) to eight healthy drug-free male volunteers, concentrations of AVP in plasma increased significantly at 1, 2, and 4 hours. Although no relation between plasma MDMA and AVP was found on an examination of the entire data set over the 24-hour study period, a statistically significant negative correlation was observed at 1 hour. As this occurred at a time when both AVP and MDMA concentrations were rising, it was postulated that a metabolite, or metabolites, could primarily be responsible for the increase in AVP. To test this hypothesis we examined the effect of MDMA and five of its metabolites, in the dose range 0.1-1,000 nM, on AVP release from the isolated rat hypothalamus. All compounds tested were found to increase AVP release (using 10 nM and 1,000 nM concentrations), with 4-hydroxy-3-methoxymethamphetamine (HMMA), the major metabolite of MDMA, being the most potent, and 3,4-dihydroxymethamphetamine (DHMA) the least potent. Each compound (1,000 nM), with the exception of DHMA, also enhanced the response to 40-mM potassium stimulation. Our findings confirm that metabolites of MDMA, in addition to the parent drug, contribute to AVP secretion in vitro. Further work will demonstrate whether this is also true in vivo.


Paraquat-mediated selection for mutations in the manganese-superoxide dismutase gene sodA.
We report the unexpected result that Escherichia coli isolates containing a multicopy plasmid (pDT1.5) carrying the manganese-superoxide dismutase gene sodA were more sensitive than the wild type to paraquat-mediated growth inhibition. The pDT1.5 locus responsible for the paraquat-sensitive phenotype was delimited to a 0.6-kilobase segment by transposon Tn5 mutagenesis. Moreover, superoxide dismutase activity was the same as in the wild type in strains carrying pDT1.5::Tn5 insertions mapping to the 0.6-kilobase locus. These data identify the 0.6-kilobase segment as the locus of sodA and establish an association between growth inhibition by paraquat and the function of the plasmid-borne sodA gene.


Optimizing Digital Integrated Care via Micro-Randomized Trials.
Mobile health (mHealth) interventions are a promising tool in providing digitally mediated integrative care. They can extend care outside of the clinic by providing reminders to take medications, assisting in managing symptoms, and supporting healthy behaviors including physical activity, healthy eating, and stress management. mHealth interventions can adapt the delivery of care across time in order to optimize treatment effectiveness. Yet there exists limited empirical evidence useful to the development of adaptive mHealth interventions. This article describes a new randomized trial design, the Micro-Randomized Trial (MRT), for informing the development of mHealth interventions. We provide examples of scientific questions important to the development of an mHealth intervention, and describe how these questions can be answered using an MRT.


Mesenchymal stem cell and islet co-transplantation promotes graft revascularization and function.
Bone marrow-derived mesenchymal stem cells (MSCs) are known to produce vascular endothelial growth factor. We hypothesize that co-transplantation of MSCs and islets promotes revascularization and improves islet graft function. Lewis rat islets were infused into the liver of streptozotocin-diabetic syngeneic recipients or transplanted under the renal capsule of nonobese diabetic severe combined immunodeficiency (NOD SCID) mice with MSCs isolated from Lewis bone marrow and expanded in culture. Co-transplantation of 500 islets and 107 MSCs (islet-MSCs) reversed diabetes in all eight recipients, whereas islet-alone transplantation achieved euglycemia in 3 of 10 recipients. With 300 islets, five of nine islet-MSCs and 1 of 10 islets-alone recipients reversed diabetes. Results of intravenous glucose tolerance tests performed on day 56 were significantly better in islet-MSCs than islet-alone recipients. One week after transplantation, well-preserved islet structure and higher number of capillaries were found in the liver of islet-MSCs recipients, whereas islet-alone grafts were fragmented with very few capillaries. Islets showed a similar morphology when transplanted with MSCs in nonobese diabetic severe combined immunodeficiency mice with a significantly higher capillary per [beta]-cell ratio than that in islet-alone grafts (0.135+/-0.046 vs. 0.052+/-0.028 capillary segments per [beta]-cell, P<0.01). One week after transplantation, islets were surrounded by MSCs labeled with carboxyfluorescein succinimidyl ester or Qdot nanocrystals, and some labeled MSCs positively stained for vascular endothelial growth factor or von Willebrand factor. Our results demonstrate the improvement of islet graft morphology and function by co-transplantation with MSCs. This improvement is attributable, at least in part, to the promotion of graft revascularization mediated by MSCs.


What is special about expertise? Visual expertise reveals the interactive nature of real-world object recognition.
Ever since Diamond and Carey (1986. J. Exp. Psychol.: Gen., vol. 115, pp. 107-117) seminal work, the main model for studying expertise in visual object recognition ("visual expertise") has been face perception. The underlying assumption was that since faces may be considered the ultimate domain of visual expertise, any face-processing signature might actually be a general characteristic of visual expertise. However, while humans are clearly experts in face recognition, visual expertise is not restricted to faces and can be observed in a variety of domains. This raises the question of whether face recognition is in fact the right model to study visual expertise, and if not, what are the common cognitive and neural characteristics of visual expertise. The current perspective article addresses this question by revisiting past and recent neuroimaging and behavioural works on visual expertise. The view of visual expertise that emerges from these works is that expertise is a unique phenomenon, with distinctive neural and cognitive characteristics. Specifically, visual expertise is a controlled, interactive process that develops from the reciprocal interactions between the visual system and multiple top-down factors, including semantic knowledge, top-down attentional control, and task relevance. These interactions enable the ability to flexibly access domain-specific information at multiple scales and levels guided by multiple recognition goals. Extensive visual experience with a given object category culminates in the recruitment of these multiple systems, and is reflected in widespread neural activity, extending well beyond visual cortex, to include higher-level cortical areas.


Peripheral blood derived gene panels predict response to infliximab in rheumatoid arthritis and Crohn's disease.
Biological therapies have been introduced for the treatment of chronic inflammatory diseases including rheumatoid arthritis (RA) and Crohn's disease (CD). The efficacy of biologics differs from patient to patient. Moreover these therapies are rather expensive, therefore treatment of primary non-responders should be avoided. We addressed this issue by combining gene expression profiling and biostatistical approaches. We performed peripheral blood global gene expression profiling in order to filter the genome for target genes in cohorts of 20 CD and 19 RA patients. Then RT-quantitative PCR validation was performed, followed by multivariate analyses of genes in independent cohorts of 20 CD and 15 RA patients, in order to identify sets ofinterrelated genes that can separate responders from non-responders to the humanized chimeric anti-TNFalpha antibody infliximab at baseline. Gene panels separating responders from non-responders were identified using leave-one-out cross-validation test, and a pool of genes that should be tested on larger cohorts was created in both conditions. Our data show that peripheral blood gene expression profiles are suitable for determining gene panels with high discriminatory power to differentiate responders from non-responders in infliximab therapy at baseline in CD and RA, which could be cross-validated successfully. Biostatistical analysis of peripheral blood gene expression data leads to the identification of gene panels that can help predict responsiveness of therapy and support the clinical decision-making process.


Supervisory control of Petri nets using routing functions: starvation avoidance issues.
In this paper, we present a new point of view on supervisory control of Petri nets by using routing functions instead of the traditional control places. We first show the relation between the two notions. In the second part of the paper, we illustrate the use of routing functions by showing how to compute a routing function in order to avoid starvation in general Petri nets. This control uses a continuous version of the net and a description of the evolution of the net under the form of linear algebraic equations. As for the computational part, we use algebraic polynomial geometry in the continuous case and Diophantine equations for the discrete version of the Petri net under study.


Overexpression of Slug is associated with malignant progression of esophageal adenocarcinoma.
To characterise expression of known E-cadherin repressors; Snail, Slug and Twist in the development of esophageal adenocarcinoma. E-cadherin, Slug, Snail and Twist mRNA expression in Barrett's metaplasia and esophageal adenocarcinoma specimens was examined by real-time reverse transcription-polymerase chain reaction (RT-PCR). Semi-quantitative immunohistochemistry was used to examine cellular localisation and protein levels. The effect of Slug on epithelial mesenchymal transition (EMT) markers was examined by transfection of Slug into an adenocarcinoma line OE33. Cellular localisation of Slug in Barrett's metaplasia was largely cytoplasmic whilst in adenocarcinoma it was nuclear. Semi-quantitative analysis indicated that Slug was more abundant in adenocarcinoma compared to matched Barrett's metaplastic specimens. Snail and Twist were expressed in adenocarcinoma but were cytoplasmic in location and not induced compared to Barrett's mucosa. These observations were supported by mRNA studies where only Slug mRNA was shown to be over-expressed in adenocarcinoma and inversely correlated to E-cadherin expression. Overexpression of Slug in OE33 mediated E-cadherin repression and induced the mesenchymal markers vimentin and fibronectin. Progression to adenocarcinoma is associated with increased Slug expression and this may represent a mechanism of E-cadherin silencing.


A Deep Learning-based in silico Framework for Optimization on Retinal Prosthetic Stimulation.
We propose a neural network-based framework to optimize the perceptions simulated by the in silico retinal implant model pulse2percept. The overall pipeline consists of a trainable encoder, a pre-trained retinal implant model and a pre-trained evaluator. The encoder is a U-Net, which takes the original image and outputs the stimulus. The pre-trained retinal implant model is also a U-Net, which is trained to mimic the biomimetic perceptual model implemented in pulse2percept. The evaluator is a shallow VGG classifier, which is trained with original images. Based on 10,000 test images from the MNIST dataset, we show that the convolutional neural network-based encoder performs significantly better than the trivial downsampling approach, yielding a boost in the weighted F1-Score by 36.17% in the pre-trained classifier with 6×10 electrodes. With this fully neural network-based encoder, the quality of the downstream perceptions can be fine-tuned using gradient descent in an end-to-end fashion.